PROJECT SUMMARY/ABSTRACT This proposal details a five-year research and career development plan for Jeremy R. Beitler, MD, MPH, a pulmonary intensivist and Assistant Professor at the University of California, San Diego. The overall focus of his research is to quantify at bedside key biomechanical determinants of lung injury in patients with ARDS to inform development of novel lung-protective strategies tailored to patient-specific risk. This K23 award will provide the necessary support for Dr. Beitler to attain the following goals: (1) to acquire a foundation in biomechanics and bioinstrumentation; (2) to gain proficiency in physiological signal processing; (3) to expand his expertise in ARDS lung biology; and (4) to gain proficiency in longitudinal data analysis. Dr. Beitler has assembled a highly collaborative team of senior investigators to support his research training and career development. His primary mentor, Dr. Atul Malhotra, is expert in respiratory physiology, signal processing, and ventilatory control, and co-mentor Dr. Michael Matthay is a preeminent clinical-translational investigator in biology of acute lung injury. His training team also includes expert consultants in biomechanics (Dr. Andrew McCulloch) and longitudinal data analysis (Dr. Sonia Jain). Mechanical ventilation with low tidal volumes decreases lung injury and improves survival in patients with ARDS. Breath stacking dyssynchrony (BSD) describes a patient-ventilator interaction in which consecutive machine inspiratory cycles occur with incomplete exhalation between them, causing higher tidal volumes than intended. At least two mechanistically distinct BSD subtypes exist, differentiated by the timing and pattern of neural inspiration. Distinguishing between BSD subtypes may be important for developing effective interventions that (1) minimize risk of ventilator-induced lung injury and (2) avoid side-effects of deep sedation often prescribed in attempt to abate BSD. Dr. Beitler?s central hypothesis is that BSD subtypes are associated with dissimilar clinical factors but have similar implications for lung injury in ARDS. Dr. Beitler will evaluate the relationship of BSD subtypes with hypercapnia (Aim 1) and deep sedation (Aim 2), two clinically discernable factors that could serve as therapeutic targets for future study. Dr. Beitler also will identify the exposure-response relationship of BSD with lung injury, as measured by plasma biomarkers of alveolar injury (Aim 3). To achieve these aims, Dr. Beitler will build a prospective cohort of patients with ARDS in whom airflow, airway pressure, and esophageal pressure are measured continuously to quantify BSD by subtype. Repeated measures of plasma biomarkers will be used to gauge lung injury. This research and career development plan provides Dr. Beitler a strong foundation to become an independent investigator studying BSD subtype-specific therapies to curb unnecessary sedative use and improve adherence to lung-protective ventilation in ARDS.